This invention pertains generally to treating diseases characterized by angiogenesis including cancer. More specifically, the invention described herein pertains to treating diseases characterized by activity of vascular endothelial growth factor receptor tyrosine kinases. The present invention provides, small molecule inhibitors of vascular endothelial growth factor receptor tyrosine kinase, pharmaceutical formulations containing such inhibitors, methods of treating patients with such pharmaceutical formulations, and to methods of preparing such pharmaceutical formulations and inhibitors.
Capillaries reach into almost all tissues of the human body and supply tissues with oxygen and nutrients as well as removing waste products. Under typical conditions, the endothelial cells lining the capillaries do not divide, and capillaries, therefore, do not normally increase in number or size in a human adult. Under certain normal conditions, however, such as when a tissue is damaged, or during certain parts of the menstrual cycle, the capillaries begin to proliferate rapidly. This process of forming new capillaries from pre-existing blood vessels is known as angiogenesis or neovascularization. See Folkman, J. Scientific American 275, 150-154 (1996). Angiogenesis during wound healing is an example of pathophysiological neovascularization during adult life. During wound healing, the additional capillaries provide a supply of oxygen and nutrients, promote granulation tissue, and aid in waste removal. After termination of the healing process, the capillaries normally regress. Lymboussaki, A. xe2x80x9cVascular Endothelial Growth Factors and their Receptors in Embryos, Adults, and in Tumorsxe2x80x9d Academic Dissertation, University of Helsinki, Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, (1999).
Angiogenesis also plays an important role in the growth of cancer cells. It is known that once a nest of cancer cells reaches a certain size, roughly 1 to 2 mm in diameter, the cancer cells must develop a blood supply in order for the tumor to grow larger as diffusion will not be sufficient to supply the cancer cells with enough oxygen and nutrients. Thus, inhibition of angiogenesis is expected to halt the growth of cancer cells.
Receptor tyrosine kinases (RTKs) are transmembrane polypeptides that regulate developmental cell growth and differentiation, remodeling and regeneration of adult tissues. Mustonen, T. et al., J. Cell Biology 129, 895-898 (1995); van der Geer, P. et al. Ann Rev. Cell Biol. 10, 251-337 (1994). Polypeptide ligands known as growth factors or cytokines, are known to activate RTKs. Signaling RTKs involves ligand binding and a shift in conformation in the external domain of the receptor resulting in its dimerization. Lymboussaki, A. xe2x80x9cVascular Endothelial Growth Factors and their Receptors in Embryos, Adults, and in Tumorsxe2x80x9d Academic Dissertation, University of Helsinki, Molecular/Cancer Biology Laboratory and Department of Pathology, Haartman Institute, (1999); Ullrich, A. et al., Cell 61, 203-212 (1990). Binding of the ligand to the RTK results in receptor trans-phosphorylation at specific tyrosine residues and subsequent activation of the catalytic domains for the phosphorylation of cytoplasmic substrates. Id.
Two subfamilies of RTKs are specific to the vascular endothelium. These include the vascular endothelial growth factor (VEGF) subfamily and the Tie receptor subfamily. Class III RTKs include VEGFR-1, VEGFR-2, and VEGFR-3. Shibuya, M. et al., Oncogene 5, 519-525 (1990); Terman, B. et al., Oncogene 6, 1677-1683 (1991); Aprelikova, O. et al., Cancer Res. 52, 746-748 (1992).
Members of the VEGF subfamily have been described as being able to induce vascular permeability and endothelial cell proliferation and further identified as a major inducer of angiogenesis and vasculogenesis. Ferrara, N. et al., Endocrinol. Rev. 18, 4-25 (1997). VEGF is known to specifically bind to RTKs including VEGFR-1 and VEGFR-2. DeVries, C. et al., Science 255, 989-991 (1992); Quinn, T. et al., Proc. Natl. Acad. Sci. 90, 7533-7537 (1993). VEGF stimulates the migration and proliferation of endothelial cells and induces angiogenesis both in vitro and in vivo. Connolly, D. et al., J. Biol. Chem. 264, 20017-20024 (1989); Connolly, D. et al., J. Clin. Invest. 84, 1470-1478 (1989); Ferrara, N. et al., Endocrino. Rew. 18, 4-25 (1997); Leung, D. et al., Science 246, 1306-1309 (1989); Plouet, J. et al., EMBO J 8, 3801-3806 (1989).
Because angiogenesis is known to be critical to the growth of cancer and to be controlled by VEGF and VEGF-RTK, substantial efforts have been undertaken to develop therapeutics that are antagonists of VEGF-RTK to thereby inhibit or retard angiogenesis, and, hopefully, interfere or stop tumor proliferation.
A wide variety of chemical compounds and compositions have been reported as having activity against one of more the VEGF-RTKs. Examples include quinoline derivatives such as described in WO 98/13350, aminonicotinamide derivatives (see, e.g., WO 01/55114), antisense compounds (see, e.g., WO 01/52904), peptidomimetics (see, e.g., WO 01/52875), quinazoline derivatives (see, e.g., U.S. Pat. No. 6,258,951) monoclonal antibodies (see, e.g., EP 1 086 705 A1), various 5,10,15,20-tetraaryl-porphyrins and 5,10,15-triaryl-corroles (see, e.g., WO 00/27379), heterocyclic alkanesulfonic and alkane carboxylic acid derivatives (see, e.g., DE19841985), oxindolylquinazoline derivatives (see, e.g., WO 99/10349), 1,4-diazaanthracine derivatives (see, e.g., U.S. Pat. No. 5,763,441), and cinnoline derivatives (see, e.g., WO 97/34876), and various indazole compounds (see, e.g., WO 01/02369 and WO 01/53268).
Various indolyl substituted compounds have recently been disclosed in WO 01/29025, WO 01/62251, and WO 01/62252, and various benzimidazolyl compounds have recently been disclosed in WO 01/28993. These compounds are reportedly capable of inhibiting, modulating, and/or regulating signal transduction of both receptor-type and non-receptor tyrosine kinases. Some of the disclosed compounds contain a quinolone fragment bonded to the indolyl or benzimidazolyl group.
The synthesis of 4-hydroxy quinolone and 4-hydroxy quinoline derivatives is disclosed in a number of references. For example, Ukrainets et al. have disclosed the synthesis of 3-(benzimidazol-2-yl)-4-hydroxy-2-oxo-1,2-dihydroquinoline. Ukrainets, I. et al., Tet. Lett. 42, 7747-7748 (1995); Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 2, 239-241(1992). Ukrainets has also disclosed the synthesis, anticonvulsive and antithyroid activity of other 4-hydroxy quinolones and thio analogs such as 1H-2-oxo-3-(2-benzimidazolyl)-4-hyrdoxyquinoline. Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 1, 105-108 (1993); Ukrainets, I. et al., Khimiya Geterotsiklicheskikh Soedinii, 8, 1105-1108 (1993); Ukrainets, I. et al., Chem. Heterocyclic Comp. 33, 600-604, (1997).
The synthesis of various quinoline derivatives is disclosed in WO 97/48694. These compounds are disclosed as capable of binding to nuclear hormone receptors and being useful for stimulating osteoblast proliferation and bone growth. The compounds are also disclosed as being useful in the treatment or prevention of diseases associated with nuclear hormone receptor families.
Various quinoline derivatives in which the benzene ring of the quinolone is substituted with a sulfur group are disclosed in WO 92/18483. These compounds are disclosed as being useful in pharmaceutical formulations and as medicaments.
Quinolone and coumarin derivatives have been disclosed as having use in a variety of applications unrelated to medicine and pharmaceutical formulations. References that describe the preparation of quinolone derivatives for use in photopolymerizable compositions or for luminescent properties include: U.S. Pat. No. 5,801,212 issued to Okamoto et al.; JP 8-29973; JP 7-43896; JP 6-9952; JP 63-258903; EP 797376; and DE 23 63 459.
Despite the exploration of a variety of chemistries to provide VEGF-RTK-antagonist therapies, a continuing need exists for compounds that inhibit the proliferation of capillaries, inhibit the growth of tumors, and/or inhibit vascular endothelial growth factor receptor tyrosine kinase and pharmaceutical formulations that contain such compounds. A need also exists for methods for administering such compounds and pharmaceutical formulations to patients in need thereof.
The present invention provides compounds, pharmaceutical formulations including the compounds, methods of preparing the pharmaceutical formulations, and methods of treating patients with the pharmaceutical formulations and compounds.
The present invention provides a first group of compounds having the structure I. The invention also provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure I has the following formula: 
where, in the first group of compounds:
Y is selected from xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted saturated heterocyclyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 and R14 may be the same or different and are independently selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94N(aryl)(heterocyclyl), xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, or substituted or unsubstituted heterocyclylalkyl groups;
R11 is selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94N(aryl)(heterocyclyl) groups, xe2x80x94O-alkyl groups, O-aryl groups, heterocyclyloxyalkyl groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, or xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, or xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryloxy groups, heterocyclyloxy groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
The invention provides a second group of compounds including compounds having the structure I, tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers.
In the second group of compounds:
Y is selected from xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted saturated heterocyclyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, and tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, and tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 is selected from the group consisting of xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, or substituted or unsubstituted heterocyclylalkyl groups;
R11 is selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94O-alkyl groups, O-aryl groups, substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R14 is selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryloxy groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
The invention provides a third group of compounds including compounds having the structure I, tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers.
In the third group of compounds:
Y is selected from xe2x80x94OH, SH, alkylthio groups, arylthio groups, xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, xe2x80x94CN, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 and R14 may be the same or different and are independently selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R11 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups ,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In the third group of compounds, at least one of R5, R6, R7, or R8 is selected from substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted saturated heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; xe2x80x94OR19 groups where R19 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted and unsubstituted heterocyclyloxyalkyl groups; xe2x80x94NR20R21 groups where R20 is selected from substituted or unsubstituted heterocyclyl groups; xe2x80x94NR20R21 groups where R21 is selected from substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-aryl groups,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; or xe2x80x94C(xe2x95x90O)R25 groups where R25 is selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted aryl groups, substituted or unsubstituted aryloxy groups, or substituted or unsubstituted heterocyclyl groups.
The invention provides a fourth group of compounds having the structure I, tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers.
In the fourth group of compounds:
Y is selected from xe2x80x94OH, SH, alkylthio groups, arylthio groups, xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR1 2R13 groups, xe2x80x94CN, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 and R14 may be the same or different and are independently selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R11 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH (aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups ,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In the fourth group of compounds, at least one of R1, R2, R3, or R4 is an xe2x80x94OR15 group and R15 is selected from substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, or substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups.
Preferred compounds in any of the first, second, or third groups described above are provided in which Z is an xe2x80x94NR14. Preferred compound of the fourth group are also provided in which Z is an xe2x80x94NR10 group.
Preferred compounds according to the first, second, third, and fourth groups of compounds are provided in which Y is an xe2x80x94OR10 group, an xe2x80x94NR12R13 group, or a substituted or unsubstituted alkynyl group.
Other preferred compounds of the first, second, third, and fourth groups are provided in which R1 is selected from H, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyloxy groups, or substituted or unsubstituted heterocyclyl groups.
Still further provided are compounds of the first, second, third, and fourth groups in which R2 is selected from the group consisting of H, F, Cl, xe2x80x94NO2, substituted and unsubstituted heterocyclylalkoxy groups, and substituted and unsubstituted heterocyclyl groups.
Still further provided are compounds of the first, second, third, and fourth groups in which R6 or R7 is an alkyl group. Still further preferred compounds of the four groups are those in which R6 or R7 is an xe2x80x94OR19 group and R19 is an alkyl group, an aryl group, a heterocyclyl group, or a heterocyclylalkyl group.
Preferred compounds of the fourth group of compounds are provided in which R1 is an xe2x80x94OR15 group and R15 is selected from substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, or substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups.
The invention further provides compounds having the structure II. The invention provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure II has the following formula 
where:
Y is selected from H, xe2x80x94OH, xe2x80x94OR10 groups, xe2x80x94SH, xe2x80x94SR11 groups, xe2x80x94NR12R13 groups, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R14 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
X1, X2, X3, and X4 are selected from C or N, and at least one of X1, X2, X3, and X4 is N;
R1, R2, R3, R4, R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, xe2x80x94C(xe2x95x90O)R18 groups, xe2x80x94SH, xe2x80x94SR19 groups, xe2x80x94S(xe2x95x90O)R20 groups, S(xe2x95x90O)2R21 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; R5 is absent or is H if X1 is N; R6 is absent or is H if X2 is N; R7 is absent or is H if X3 is N; and R8 is absent or is H if X4 is N;
R9 is selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R11 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R14 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or xe2x80x94N(aryl)(heterocyclyl) groups;
R12 and R13 may join together to form a 5 to 7 membered saturated or unsaturated, substituted or unsubstituted N-containing ring;
R15 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, or xe2x80x94NH2 groups;
R16 and R17 may join together to form a 5 to 7 membered saturated or unsaturated, substituted or unsubstituted N-containing ring; and
R18, R20, and R21 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups.
Preferred compounds having structure II are also provided where Y is selected from H, xe2x80x94OH, xe2x80x94OR10 groups, or xe2x80x94NR12R13 groups.
Still other preferred compounds having structure II are provided where at least two of X1, X2, X3, and X4 are C and the corresponding substituents R5, R6, R7, and R8 are hydrogen, and at least one of X1, X2, X3, and X4 is N, and the rest of the compound is consistent with any of the above-described compounds.
Still other more preferred compounds of structure II are provided in which R6 or R7 is an alkyl group and the rest of the compound is consistent with any of the above-described compounds.
Still other compounds of structure II are provided in which R6 or R7 is an xe2x80x94OR15 group and R15 is an alkyl, aryl, heterocyclyl, or heterocyclylalkyl group and the rest of the molecule is consistent with any of the above-described compounds.
Still further compounds having the formula of structure II are provided in which R1 is selected from H, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyloxy groups, or substituted or unsubstituted heterocyclyl groups.
Still other compounds having the Structure II are provided in which In other compounds having the structure II, R2 is selected from H, F, Cl, xe2x80x94NO2, substituted or unsubstituted heterocyclyl groups, or substituted or unsubstituted heterocyclylalkoxy groups.
Pharmaceutical formulations according to the present invention are provided which include any of the compounds described above in combination with a pharmaceutically acceptable carrier.
A method of treating a patient in need of an inhibitor of vascular endothelial growth factor receptor tyrosine kinase is provided which includes administering an effective amount of the pharmaceutical formulation according to the present invention to a patient in need thereof.
Further objects, features and advantages of the invention will be apparent from the following detailed description.
The present invention provides novel compounds that act as antagonists of receptor tyrosine kinases, and, more particularly, as inhibitors of bFGF and/or VEGF-RTK function. The compounds provided herein can be formulated into pharmaceutical formulations that are useful in treating patients with a need for an inhibitor of VEGF-RTK, especially, in particular embodiments, to provide compositions and methods for reducing capillary proliferation and in the treatment of cancer.
The following abbreviations and definitions are used throughout this application:
xe2x80x9cVEGFxe2x80x9d is an abbreviation that stands for vascular endothelial growth factor.
xe2x80x9cRTKxe2x80x9d is an abbreviation that stands for receptor tyrosine kinase.
xe2x80x9cVEGF-RTKxe2x80x9d is an abbreviation that stands for vascular endothelial growth factor receptor tyrosine kinase.
xe2x80x9cFlt-1xe2x80x9d is an abbreviation that stands for fms-like tyrosine kinase-1, also known as vascular endothelial growth factor receptor-1 or xe2x80x9cVEGFR1xe2x80x9d.
xe2x80x9cKDRxe2x80x9d is an abbreviation that stands for kinase-insert domain-containing receptor, also known as vascular endothelial growth factor receptor-2 or xe2x80x9cVEGFR2xe2x80x9d.
xe2x80x9cbFGFxe2x80x9d is an abbreviation that stands for basic fibroblast growth factor.
xe2x80x9cbFGFRxe2x80x9d is an abbreviation that stands for basic fibroblast growth factor receptor.
Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
The phrase xe2x80x9cunsubstituted alkylxe2x80x9d refers to alkyl groups that do not contain heteroatoms. Thus the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes branched chain isomers of straight chain alkyl groups, including but not limited to, the following which are provided by way of example: xe2x80x94CH(CH3)2, xe2x80x94CH(CH3)(CH2CH3), xe2x80x94CH(CH2CH3)2, xe2x80x94C(CH3)3, xe2x80x94C(CH2CH3)3, xe2x80x94CH2CH(CH3)2, xe2x80x94CH2CH(CH3)(CH2CH3), xe2x80x94CH2CH(CH2CH3)2, xe2x80x94CH2C(CH3)3, xe2x80x94CH2C(CH2CH3)3, xe2x80x94CH(CH3)CH(CH3)(CH2CH3), xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH2CH2CH(CH3)(CH2CH3), xe2x80x94CH2CH2CH(CH2CH3)2, xe2x80x94CH2CH2C(CH3)3, xe2x80x94CH2CH2C(CH2CH3)3, xe2x80x94CH(CH3)CH2CH(CH3)2, xe2x80x94CH(CH3)CH(CH3)CH(CH3)2, xe2x80x94CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others. The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and branched chain alkyl groups as defined above. The phrase also includes polycyclic alkyl groups such as, but not limited to, adamantyl norbornyl, and bicyclo[2.2.2]octyl and such rings substituted with straight and branched chain alkyl groups as defined above. Thus, the phrase unsubstituted alkyl groups includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound. Preferred unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups having 1 to 20 carbon atoms. More preferred such unsubstituted alkyl groups have from 1 to 10 carbon atoms while even more preferred such groups have from 1 to 5 carbon atoms. Most preferred unsubstituted alkyl groups include straight and branched chain alkyl groups having from 1 to 3 carbon atoms and include methyl, ethyl, propyl, and xe2x80x94CH(CH3)2.
The phrase xe2x80x9csubstituted alkylxe2x80x9d refers to an unsubstituted alkyl group as defined above in which one or more bonds to a carbon(s) or hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but not limited to, a halogen atom in halides such as F, Cl, Br, and I; and oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom is replaced by a bond to a heteroatom such as oxygen in carbonyl, carboxyl, and ester groups; nitrogen in groups such as imines, oximes, hydrazones, and nitriles. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more. bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to fluorine atoms. One example of a substituted alkyl group is the trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group. Other alkyl groups include those in which one or more bonds to a carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the substituted alkyl group contains a hydroxyl, alkoxy, aryloxy group, or heterocyclyloxy group. Still other alkyl groups include alkyl groups that have an amine, alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine,diarylamine, heterocyclylamine, (alkyl)(heterocyclyl)amine, (aryl)(heterocyclyl)amine, or diheterocyclylamine group.
The phrase xe2x80x9cunsubstituted arylxe2x80x9d refers to aryl groups that do not contain heteroatoms. Thus the phrase includes, but is not limited to, groups such as phenyl, biphenyl, anthracenyl, naphthenyl by way of example. Although the phrase xe2x80x9cunsubstituted arylxe2x80x9d includes groups containing condensed rings such as naphthalene, it does not include aryl groups that have other groups such as alkyl or halo groups bonded to one of the ring members, as aryl groups such as tolyl are considered herein to be substituted aryl groups as described below. A preferred unsubstituted aryl group is phenyl. Unsubstituted aryl groups may be bonded to one or more carbon atom(s), oxygen atom(s), nitrogen atom(s), and/or sulfur atom(s) in the parent compound, however.
The phrase xe2x80x9csubstituted aryl groupxe2x80x9d has the same meaning with respect to unsubstituted aryl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. However, a substituted aryl group also includes aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above and also includes aryl groups in which one or more aromatic carbons of the aryl group is bonded to a substituted and/or unsubstituted alkyl, alkenyl, or alkynyl group as defined herein. This includes bonding arrangements in which two carbon atoms of an aryl group are bonded to two atoms of an alkyl, alkenyl, or alkynyl group to define a fused ring system (e.g. dihydronaphthyl or tetrahydronaphthyl). Thus, the phrase xe2x80x9csubstituted arylxe2x80x9d includes, but is not limited to tolyl, and hydroxyphenyl among others.
The phrase xe2x80x9cunsubstituted alkenylxe2x80x9d refers to straight and branched chain and cyclic groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Examples include, but are not limited to vinyl, xe2x80x94CHxe2x95x90C(H)(CH3), xe2x80x94CHxe2x95x90C(CH3)2, xe2x80x94C(CH3)xe2x95x90C(H)2, xe2x80x94C(CH3)xe2x95x90C(H)(CH3), xe2x80x94C(CH2CH3)xe2x95x90CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
The phrase xe2x80x9csubstituted alkenylxe2x80x9d has the same meaning with respect to unsubstituted alkenyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon double bonded to another carbon and those in which one of the non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond to another carbon.
The phrase xe2x80x9cunsubstituted alkynylxe2x80x9d refers to straight and branched chain groups such as those described with respect to unsubstituted alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms. Examples include, but are not limited to xe2x80x94Cxe2x89xa1C(H), xe2x80x94Cxe2x89xa1C(CH3), xe2x80x94Cxe2x89xa1C(CH2CH3), xe2x80x94C(H2)Cxe2x89xa1C(H), xe2x80x94C(H)2Cxe2x89xa1C(CH3), and xe2x80x94C(H)2Cxe2x89xa1C(CH2CH3) among others.
The phrase xe2x80x9csubstituted alkynylxe2x80x9d has the same meaning with respect to unsubstituted alkynyl groups that substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is bonded to a carbon triple bonded to another carbon and those in which a non-carbon or non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
The phrase xe2x80x9cunsubstituted aralkylxe2x80x9d refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl (xe2x80x94CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a phenyl group, such as if the carbon of the methyl were bonded to a carbon of benzene, then the compound is an unsubstituted aralkyl group (i.e., a benzyl group). Thus the phrase includes, but is not limited to, groups such as benzyl, diphenylmethyl, and 1-phenylethyl (xe2x80x94CH(C6H5)(CH3)) among others.
The phrase xe2x80x9csubstituted aralkylxe2x80x9d has the same meaning with respect to unsubstituted aralkyl groups that substituted aryl groups had with respect to unsubstituted aryl groups. However, a substituted aralkyl group also includes groups in which a carbon or hydrogen bond of the alkyl part of the group is replaced by a bond to a non-carbon or a non-hydrogen atom. Examples of substituted aralkyl groups include, but are not limited to, xe2x80x94CH2C(xe2x95x90O)(C6H5), and xe2x80x94CH2(2-methylphenyl) among others.
The phrase xe2x80x9cunsubstituted heterocyclylxe2x80x9d refers to both aromatic and nonaromatic ring compounds including monocyclic, bicyclic, and polycyclic ring compounds such as, but not limited to, quinuclidyl, containing 3 or more ring members of which one or more is a heteroatom such as, but not limited to, N, O, and S. Although the phrase xe2x80x9cunsubstituted heterocyclylxe2x80x9d includes condensed heterocyclic rings such as benzimidazolyl, it does not include heterocyclyl groups that have other groups such as alkyl or halo groups bonded to one of the ring members as compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups. Examples of heterocyclyl groups include, but are not limited to: unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazolyl, (e.g. 1H-tetrazolyl, 2H tetrazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms such as, but not limited to, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl; unsaturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, oxazolyl, isoxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms such as, but not limited to, morpholinyl; unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl, benzoxazinyl (e.g. 2H-1,4-benzoxazinyl etc.); unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolyl, isothiazolyl, thiadiazolyl (e.g. 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.); saturated 3 to 8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, thiazolodinyl; saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as, but not limited to, thienyl, dihydrodithiinyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran; unsaturated condensed heterocyclic rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms such as, but not limited to, benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (e.g. 2H-3,4-dihydrobenzothiazinyl, etc.), unsaturated 3 to 8 membered rings containing oxygen atoms such as, but not limited to furyl; unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms such as benzodioxolyl (e.g. 1,3-benzodioxoyl, etc.); unsaturated 3 to 8 membered rings containing an oxygen atom and 1 to 2 sulfur atoms such as, but not limited to, dihydrooxathiinyl; saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms such as 1,4-oxathiane; unsaturated condensed rings containing 1 to 2 sulfur atoms such as benzothienyl, benzodithiinyl; and unsaturated condensed heterocyclic rings containing an oxygen atom and 1 to 2 oxygen atoms such as benzoxathiinyl. Heterocyclyl group also include those described above in which one or more S atoms in the ring is double-bonded to one or two oxygen atoms (sulfoxides and sulfones). For example, heterocyclyl groups include tetrahydrothiophene, tetrahydrothiophene oxide, and tetrahydrothiophene 1,1-dioxide. Preferred heterocyclyl groups contain 5 or 6 ring members. More preferred heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazine, oxazolidin-2-one, pyrrolidin-2-one, oxazole, quinuclidine, thiazole, isoxazole, furan, and tetrahydrofuran.
The phrase xe2x80x9csubstituted heterocyclylxe2x80x9d refers to an unsubstituted heterocyclyl group as defined above in which one of the ring members is bonded to a non-hydrogen atom such as described above with respect to substituted alkyl groups and substituted aryl groups. Examples, include, but are not limited to, 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methyl piperazinyl, and 2-chloropyridyl among others.
The phrase xe2x80x9cunsubstituted heterocyclylalkylxe2x80x9d refers to unsubstituted alkyl groups as defined above in which a hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to a heterocyclyl group as defined above. For example, methyl (xe2x80x94CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, such as if the carbon of the methyl were bonded to carbon 2 of pyridine (one of the carbons bonded to the N of the pyridine) or carbons 3 or 4 of the pyridine, then the compound is an unsubstituted heterocyclylalkyl group.
The phrase xe2x80x9csubstituted heterocyclylalkylxe2x80x9d has the same meaning with respect to unsubstituted heterocyclylalkyl groups that substituted aralkyl groups had with respect to unsubstituted aralkyl groups. However, a substituted heterocyclylalkyl group also includes groups in which a non-hydrogen atom is bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group such as, but not limited to, a nitrogen atom in the piperidine ring of a piperidinylalkyl group.
The phrase xe2x80x9cunsubstituted alkylaminoalkylxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above. For example, methyl (xe2x80x94CH3) is an unsubstituted alkyl group. If a hydrogen atom of the methyl group is replaced by a bond to a nitrogen atom that is bonded to a hydrogen atom and an ethyl group, then the resulting compound is xe2x80x94CH2xe2x80x94N(H)(CH2CH3) which is an unsubstituted alkylaminoalkyl group.
The phrase xe2x80x9csubstituted alkylaminoalkylxe2x80x9d refers to an unsubstituted alkylaminoalkyl group as defined above except where one or more bonds to a carbon or hydrogen atom in one or both of the alkyl groups is replaced by a bond to a non-carbon or non-hydrogen atom as described above with respect to substituted alkyl groups except that the bond to the nitrogen atom in all alkylaminoalkyl groups does not by itself qualify all alkylaminoalkyl groups as being substituted. However, substituted alkylaminoalkyl groups does include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.
The phrase xe2x80x9cunsubstituted dialkylaminoalkylxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to two other similar or different unsubstituted alkyl groups as defined above.
The phrase xe2x80x9csubstituted dialkylaminoalkylxe2x80x9d refers to an unsubstituted dialkylaminoalkyl group as defined above in which one or more bonds to a carbon or hydrogen atom in one or more of the alkyl groups is replaced by a bond to a non-carbon and non-hydrogen atom as described with respect to substituted alkyl groups. The bond to the nitrogen atom in all dialkylaminoalkyl groups does not by itself qualify all dialkylaminoalkyl groups as being substituted.
The phrase xe2x80x9cunsubstituted heterocyclyloxyalkylxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to an unsubstituted heterocyclyl group as defined above.
The phrase xe2x80x9csubstituted heterocyclyloxyalkylxe2x80x9d refers to an unsubstituted heterocyclyloxyalkyl group as defined above in which a bond to a carbon or hydrogen group of the alkyl group of the heterocyclyloxyalkyl group is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups or in which the heterocyclyl group of the heterocyclyloxyalkyl group is a substituted heterocyclyl group as defined above.
The phrase xe2x80x9cunsubstituted arylaminoalkylxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon bond or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to at least one unsubstituted aryl group as defined above.
The phrase xe2x80x9csubstituted arylaminoalkylxe2x80x9d refers to an unsubstituted arylaminoalkyl group as defined above except where either the alkyl group of the arylaminoalkyl group is a substituted alkyl group as defined above or the aryl group of the arylaminoalkyl group is a substituted aryl group except that the bonds to the nitrogen atom in all arylaminoalkyl groups does not by itself qualify all arylaminoalkyl groups as being substituted. However, substituted arylaminoalkyl groups does include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.
The phrase xe2x80x9cunsubstituted heterocyclylaminoalkylxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to a nitrogen atom which is bonded to at least one unsubstituted heterocyclyl group as defined above.
The phrase xe2x80x9csubstituted heterocyclylaminoalkylxe2x80x9d refers to unsubstituted heterocyclylaminoalkyl groups as defined above in which the heterocyclyl group is a substituted heterocyclyl group as defined above and/or the alkyl group is a substituted alkyl group as defined above. The bonds to the nitrogen atom in all heterocyclylaminoalkyl groups does not by itself qualify all heterocyclylaminoalkyl groups as being substituted. However, substituted heterocyclylaminoalkyl groups do include groups in which the hydrogen bonded to the nitrogen atom of the group is replaced with a non-carbon and non-hydrogen atom.
The phrase xe2x80x9cunsubstituted alkylaminoalkoxyxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to a hydrogen atom and an unsubstituted alkyl group as defined above.
The phrase xe2x80x9csubstituted alkylaminoalkoxyxe2x80x9d refers to unsubstituted alkylaminoalkoxy groups as defined above in which a bond to a carbon or hydrogen atom of the alkyl group bonded to the oxygen atom which is bonded to the parent compound is replaced by one or more bonds to a non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and/or if the hydrogen bonded to the amino group is bonded to a non-carbon and non-hydrogen atom and/or if the alkyl group bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all alkylaminoalkoxy groups does not by itself qualify all such groups as substituted alkylaminoalkoxy groups.
The phrase xe2x80x9cunsubstituted dialkylaminoalkoxyxe2x80x9d refers to an unsubstituted alkyl group as defined above in which a carbon or hydrogen bond is replaced by a bond to an oxygen atom which is bonded to the parent compound and in which another carbon or hydrogen bond of the unsubstituted alkyl group is bonded to a nitrogen atom which is bonded to two other similar or different unsubstituted alkyl groups as defined above.
The phrase xe2x80x9csubstituted dialkylaminoalkoxyxe2x80x9d refers to an unsubstituted dialkylaminoalkoxy group as defined above in which a bond to a carbon or hydrogen atom of the alkyl group bonded to the oxygen atom which is bonded to the parent compound is replaced by one or more bonds to a non-carbon and non-hydrogen atoms as discussed above with respect to substituted alkyl groups and/or if one or more of the alkyl groups bonded to the nitrogen of the amine is bonded to a non-carbon and non-hydrogen atom as described above with respect to substituted alkyl groups. The presence of the amine and alkoxy functionality in all dialkylaminoalkoxy groups does not by itself qualify all such groups as substituted dialkylaminoalkoxy groups.
The phrase xe2x80x9cunsubstituted heterocyclyloxyxe2x80x9d refers to a hydroxyl group (xe2x80x94OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise unsubstituted heterocyclyl group as defined above.
The phrase xe2x80x9csubstituted heterocyclyloxyxe2x80x9d refers to a hydroxyl group (xe2x80x94OH) in which the bond to the hydrogen atom is replaced by a bond to a ring atom of an otherwise substituted heterocyclyl group as defined above.
The term xe2x80x9cprotectedxe2x80x9d with respect to hydroxyl groups, amine groups, and sulfhydryl groups refers to forms of these functionalities which are protected from undesirable reaction with a protecting group known to those skilled in the art such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley and Sons, New York, N.Y., (3rd Edition, 1999) which can be added or removed using the procedures set forth therein. Examples of protected hydroxyl groups include, but are not limited to, silyl ethers such as those obtained by reaction of a hydroxyl group with a reagent such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane; substituted methyl and ethyl ethers such as, but not limited to methoxymethyl ether, methythiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ethers, 1-ethoxyethyl ether, allyl ether, benzyl ether; esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate, and trifluoracetate. Examples of protected amine groups include, but are not limited to, amides such as, formamide, acetamide, trifluoroacetamide, and benzamide; imides, such as phthalimide, and dithiosuccinimide; and others. Examples of protected sulfhydryl groups include, but are not limited to, thioethers such as S-benzyl thioether, and S-4-picolyl thioether; substituted S-methyl derivatives such as hemithio, dithio and aminothio acetals; and others.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d includes a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. As salts of inorganic bases, the invention includes, for example, alkali metals such as sodium or potassium; alkaline earth metals such as calcium and magnesium or aluminum; and ammonia. As salts of organic bases, the invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, and triethanolamine. As salts of inorganic acids, the instant invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. As salts of organic acids, the instant invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. As salts of basic amino acids, the instant invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.
Generally, the invention provides compounds including having the structure I. The invention also provides tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure I has the following formula: 
Preferred compounds having structure I are those within one of four groups.
In the first group of compounds:
Y is selected from xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted saturated heterocyclyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 and R14 may be the same or different and are independently selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94N(aryl)(heterocyclyl), xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, or substituted or unsubstituted heterocyclylalkyl groups;
R11 is selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94N(aryl)(heterocyclyl) groups, xe2x80x94O -alkyl groups, O-aryl groups, heterocyclyloxyalkyl groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, or xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups,
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, or xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryloxy groups, heterocyclyloxy groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In other embodiments of the invention, compounds of formula I above include a second group of compounds having the substituents described below:
Y is selected from xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted saturated heterocyclyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, and tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, and tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 is selected from the group consisting of xe2x80x94OH, substituted or unsubstituted all:oxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, or substituted or unsubstituted heterocyclylalkyl groups;
R11 is selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94O-alkyl groups, O-aryl groups, substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O) N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R14 is selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryloxy groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In another embodiment, the present invention provides a third group of compounds having the general formula I above with substituents selected from the following:
Y is selected from xe2x80x94OH, SH, alkylthio groups, arylthio groups, xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, xe2x80x94CN, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or xe2x80x94C(xe2x95x90O)R18;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 and R14 may be :he same or different and are independently selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(alkyl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R11 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)Oxe2x80x94aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In the third group of compounds, at least one of R5, R6, R7, or R8 is selected from substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted saturated heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; xe2x80x94OR19 groups where R19 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted and unsubstituted heterocyclyloxyalkyl groups; xe2x80x94NR20R21 groups where R20 is selected from substituted or unsubstituted heterocyclyl groups; xe2x80x94NR20R21 groups where R12 is selected from substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-aryl groups ,xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups; or xe2x80x94C(xe2x95x90O)R25 groups where R25 is selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted aryl groups, substituted or unsubstituted aryloxy groups, or substituted or unsubstituted heterocyclyl groups
In yet another embodiment, the present invention encompasses compounds of formula I in which the substituents described below define a fourth group of compounds:
Y is selected from xe2x80x94OH, SH, alkylthio groups, arylthio groups, xe2x80x94OR10 groups, xe2x80x94C(xe2x95x90O)xe2x80x94R11 groups, xe2x80x94NR12R13 groups, xe2x80x94CN, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substitute or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, or substituted or unsubstituted aryloxyalkyl groups;
Z is selected from O, S, or NR14 groups;
R1, R2, R3, and R4 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, or xe2x80x94C(xe2x95x90O)R18 groups;
R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94OH, xe2x80x94OR19 groups, xe2x80x94NR20R21 groups, xe2x80x94SH, xe2x80x94SR22 groups, xe2x80x94S(xe2x95x90O)R23 groups, xe2x80x94S(xe2x95x90O)2R24 groups, xe2x80x94CN, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)R25 groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups| substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R9 and R14 may be the same or different and are independently selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups;
R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C( xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
R11 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or substituted or unsubstituted aryl groups;
R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94Cxe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90C)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R15 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl, substituted or unsubstituted diheterocyclylaminoalkyl, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R16 and R20 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups;
R17 and R21 may be the same or different and are independently selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups;
R18, R23, R24, and R25 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups; and
R22 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In the fourth group of compounds, at least one of R1, R2, R3, or R4 is an xe2x80x94OR15 group and R15 is selected from substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl) aminoalkyl groups, or substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups.
In the first, second, or third group of compounds Z is preferably an xe2x80x94NR14 group, more preferably where R14 is H. Preferred compounds of the fourth group include those compounds in which Z is an xe2x80x94NR10 group, more preferably where R10 is H.
Y is preferably an xe2x80x94OR10 group, an xe2x80x94NR12R13 group, or a substituted or unsubstituted alkynyl group, or more preferably is an xe2x80x94NR12N13 group in the first, second, third, and fourth groups of compounds. In more preferred compounds of the first group, Y is a NR12R13 group and R12 is H. In more preferred compounds of the second and third groups, Y is a NR12R13 group and one or both of R12 and R13 are H.
Other preferred compounds of the first, second, and third groups include those where Y is selected from xe2x80x94N(CH3)2, xe2x80x94NH(CH3), xe2x80x94NH(CH2CH3), xe2x80x94N(CH2CH3)2, xe2x80x94NH(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94NHNH2, xe2x80x94NHN(CH3)2, xe2x80x94N(CH3)NH(CH3), xe2x80x94NH(CH2)mNH2 groups, xe2x80x94NH(CH2)mNH(alkyl) groups, xe2x80x94NH(CH2)mN(alkyl)2 groups, xe2x80x94N(alkyl)(CH2)mNH2 groups, xe2x80x94N(alkyl)(CH2)mxe2x80x94NH(alkyl) groups, xe2x80x94N(alkyl)(CH2)mN(alkyl)2 groups, xe2x80x94NH(CH2)n(heterocyclyl) groups, xe2x80x94N(alkyl)[(CH2)n(heterocyclyl)] groups, xe2x80x94NH(CH2)mOH groups, xe2x80x94NH(CH2)mOCH3 groups, xe2x80x94NHCH2CH(NH2)CH(CH3)2, xe2x80x94NH(2-aminocyclohexyl), xe2x80x94NH(cyclohexyl), xe2x80x94NHOCH3, xe2x80x94NH(N-morpholinyl), xe2x80x94NH(quinuclidyl), especially xe2x80x94NH(quinuclid-3-yl), or groups where R12 and R13 join to form a substituted or unsubstituted saturated 5 or 6 membered N-containing ring, where m is an integer ranging from 2 to 4 such as 2, 3, or 4 and n is an integer ranging from 0 to 3 such as 0, 1, 2, or 3.
More preferred compounds of the first, second, and third also include those in which Y is selected from xe2x80x94NH(5-benzimidazolyl), xe2x80x94NH(CH2)2N(CH3)2, xe2x80x94NH(CH2)2OH, xe2x80x94NH(CH2)(4-imidazolyl), xe2x80x94NH(CH2)(3-imidazolyl), xe2x80x94NH(CH2)(4xe2x80x94pyridyl), xe2x80x94NH(CH2)(2-pyridyl), xe2x80x94NH(CH2)(3-pyridyl), xe2x80x94NH(CH2)(2-tetrahydrofuranyl), xe2x80x94NH(CH2)(4-piperidinyl), xe2x80x94NH(CH2)(3-piperidinyl), xe2x80x94NH(CH2)2[2-(N-methylpyrrolidinyl)], xe2x80x94NH(CH2)2(2-pyrrolidinyl), xe2x80x94NH(CH2)[2-(N-methylpyrrolidinyl)], xe2x80x94NH(CH2)(2-pyrrolidinyl), xe2x80x94NH(3-piperidinyl), or xe2x80x94NH(3-pyrrolidinyl).
Preferred compounds of the first and second groups include those compounds where R1, R2, R3, R4, R5, R6, R7, and R8 are all H. Other preferred compounds of the first, second, third, and fourth groups include those where R1 is selected from H, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyloxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-, heterocyclyl-, or aryl-aminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkyl- or aryl-aminoalkoxy groups, substituted or unsubstituted dialkylaminoalkoxy groups, or substituted or unsubstituted diarylaminoalkoxy groups. Still other compounds of the first, second, third, and fourth groups include those in which R1 is selected from F, Cl, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-, heterocyclyl-, or aryl-aminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminoalkoxy groups, substituted or unsubstituted arylaminoalkoxy groups, substituted or unsubstituted dialkylaminoalkoxy groups, substituted or unsubstituted diarylaminoalkoxy groups, or substituted or unsubstituted (alkyl)(aryl)aminoalkoxy groups. Particular examples include: xe2x80x94OCH3, xe2x80x94OCH2CH2(N-morpholinyl), xe2x80x94N-morpholinyl, xe2x80x94N-cis-dialkylmorpholinyl, xe2x80x94Nxe2x80x94(4-alkyl)piperazinyl, xe2x80x94OCH2CH2N(alkyl)2 groups, xe2x80x94OCH2CH2NH(alkyl) groups, xe2x80x94OCH2CH2NH2, xe2x80x94OCH2CH2NH(aryl) groups, xe2x80x94OCH2CH2N(aryl)2 groups, xe2x80x94OCH2CH2N(alkyl)(aryl) groups, alkoxy groups, xe2x80x94O(4-piperidinyl), xe2x80x94O[4-(1-alkyl) piperidinyl] groups, xe2x80x94O[3-(1-alkyl)piperidinyl] groups, xe2x80x94O[3xe2x80x94quinuclidinyl], xe2x80x94OCH2(2-pyridyl), xe2x80x94OCH2(4-pyridyl), xe2x80x94O(3-pyrrolidinyl), or xe2x80x94O[3-(1-alkyl) pyrrolidinyl] groups.
Still other preferred compounds of the first, second, third, and fourth groups include those in which R2 is selected from F, Cl, xe2x80x94NO2, xe2x80x94OCH3, N-morpholinyl, xe2x80x94N-cis-dialkylmorpholinyl, xe2x80x94Nxe2x80x94(4-alkyl)piperazinyl, or xe2x80x94OCH2(2-pyridyl). Other preferred compounds of the first, second, third, and fourth groups include those where R2 is selected from H, F, Cl, xe2x80x94NO2, substituted or unsubstituted heterocyclylalkoxy groups, or substituted or unsubstituted heterocyclyl groups. Yet other preferred compounds of the first, second, third, and fourth groups include those where R2 is selected from F, Cl, xe2x80x94NO2, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-, heterocyclyl-, and aryl-aminoalkyl groups, substituted or unsubstituted dialkyl- and diaryl-aminoalkyl groups, substituted or unsubstituted alkylarylaminoalkyl groups, substituted or unsubstituted alkyl- and aryl-aminoalkoxy groups, substituted or unsubstituted dialkyl- and diaryl-aminoalkoxy groups, or substituted or unsubstituted alkylarylaminoalkoxy groups.
Still further preferred compounds of the first, second, third, and fourth groups include those where R6 is an alkyl group having from one to four carbon atoms. In other preferred compounds of the first, second, third, and fourth groups, R7 is an alkyl group haling from one to four carbon atoms. Still further preferred compounds of the four groups are those in which R6 or R7 is an xe2x80x94OR19 group and R19 is an alkyl group, an aryl group, a heterocyclyl group, or a heterocyclylalkyl group.
In still other preferred compounds of the first, second, third, and fourth groups, R6 or R7 is a xe2x80x94OCH2(CH2)q(heterocyclyl) group and q is 0, 1, 2, 3, or 4, more preferably where the heterocyclyl group of the xe2x80x94OCH2(CH2)q(heterocyclyl) group is a heterocycle selected from substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrrole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiomorpholine, substituted or unsubstituted homopiperazine, substituted or unsubstituted oxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyridine, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydrofuran, substituted or unsubstituted tetrahydrothiophene, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted benzothiazole.
In groups including heterocyclyl groups, the heterocyclyl may be attached in various ways. For example, in the xe2x80x94OCH2(CH2)q(heterocyclyl) group, the heterocyclyl group may be bonded to a methylene carbon of the xe2x80x94OCH2(CH2)q group of the xe2x80x94OCH2(CH2)q(heterocyclyl) through various ring members. By way of non-limiting example, where q is 1 and the heterocyclyl group is tetrahydrofuran, the group could be represented by the formula xe2x80x94OCH2CH2(tetrahydrofuranyl) which corresponds to the following two structures: 
where structure III represents the group that can be referred to as the xe2x80x94OCH2CH2(2-tetrahydrofuranyl) group and structure IV represents the group that can be referred to as the xe2x80x94OCH2CH2(3-tetrahydrofuranyl) group. When the heterocyclyl group is a N-containing heterocycle, such as, but not limited to piperidine, piperazine, morpholine, or pyrrolidine, the heterocycle can be bonded to the methylene carbon through a ring carbon atom or through a nitrogen atom in the ring of the N-containing heterocycle. Both of these are preferred. Where the heterocyclyl group is a piperidine and q is 2 for an xe2x80x94OCH2(CH2)q(heterocyclyl) group, the following structures are possible and preferred: 
Structure V is an example of a xe2x80x94O(CH2)3(N-piperidinyl) or xe2x80x94O(CH2)3(1-piperidinyl) group. Structure VI is an example of a xe2x80x94O(CH2)3xe2x80x94(2-piperidinyl) group. Structure VII is an example of a xe2x80x94O(CH2)3(3-piperidinyl) group. Structure VIII is an example of a xe2x80x94O(CH2)3(4-piperidinyl) group. Where the heterocyclyl group is a piperazine and q is 1 for an xe2x80x94OCH2(CH2)q(heterocyclyl) group, the following structures are possible and preferred: 
Structure IX is an example of a xe2x80x94O(CH2)2(2-piperazinyl) group, and structure X is an example of a xe2x80x94O(CH2)2(1-piperazinyl) or xe2x80x94O(CH2)2(N-piperazinyl) group. Where the heterocyclyl group is a morpholine and q is 1 for an xe2x80x94OCH2(CH2)q(heterocyclyl) group, the following structures are possible and preferred: 
Structure XI is an example of a xe2x80x94O(CH2)2(3-morpholinyl) group, structure XII is an example of a xe2x80x94O(CH2)2(4-morpholinyl) or xe2x80x94O(CH2)2(N-morpholinyl) group, and structure XIII is an example of a xe2x80x94O(CH2)2(2-morpholinyl) group. It will be observed that where the group is a pyrrolidine, and q is 1, the structures available include xe2x80x94O(CH2)2(1-pyrrolidinyl) or xe2x80x94O(CH2)2(N-pyrrolidinyl), xe2x80x94O(CH2)2(2-pyrrolidinyl), and xe2x80x94O(CH2)2(3-pyrrolidinyl).
Yet other preferred compounds of the first, second, third, and fourth groups include those where at least one of R5, R6, R7, and R8 is a substituted or unsubstituted heterocyclyl group, more specifically a substituted or unsubstituted heterocyclyl group comprising at least one O or N atom, still more particularly a substituted or unsubstituted heterocyclyl group selected from morpholine, piperazine, piperidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, pyrazole, pyrrole, thiomorpholine, thiomorpholine in which the S atom of the thiomorpholine group is bonded to one or more O atoms, homopiperazine, benzimidazole, oxazolidin-2-one, pyrrolidin-2-one, imidazole, isoxazole, oxazole, isothiazole, thiazole, thiophene, furan, pyran, tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, or pyridine.
Other preferred compounds of the first, second, third, and fourth groups include those in which at least one of R19 or R21 is selected from substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, (alkyl)(aryl)aminoalkyl groups, or substituted or unsubstituted heterocyclylalkyl groups, including: xe2x80x94CH2(CH2)pNH2 groups, xe2x80x94CH2(CH2)pNH(alkyl) groups, xe2x80x94CH2(CH2)pNH(aryl) groups, xe2x80x94CH2(CH2)pN(alkyl)2 groups, xe2x80x94CH2(CH2)pN(aryl)2 groups, xe2x80x94CH2(CH2)pN(alkyl)(aryl) groups, or xe2x80x94CH2(CH2)p(heterocyclyl) groups, wherein p is an integer ranging from 0 to 4 and the heterocyclyl group of the xe2x80x94CH2(CH2)p(heterocyclyl) group is a N-containing heterocycle selected from substituted or unsubstituted morpholine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted pyrrole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiomorpholine, substituted or unsubstituted homopiperazine, substituted or unsubstituted oxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyridine, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted benzothiazole.
Still further preferred compounds according to the first, second, third, and fourth groups include those in which R25 is selected from substituted or unsubstituted aryl groups, substituted or unsubstituted alkyl groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94NH(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, xe2x80x94N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, or N-containing heterocycles. In such compounds, the N-containing heterocycles are bonded to the carbonyl carbon of the xe2x80x94C(xe2x95x90O)xe2x80x94R25 group through either a nitrogen atom or a carbon atom in the rings of the N-containing heterocycles. In more preferred such compounds that are provided, the, N-containing heterocycle of the R25 group is selected from substituted or unsubstituted morpholine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted pyrrole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiomorpholine, substituted or unsubstituted homopiperazine, substituted or unsubstituted oxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyridine, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted benzothiazole.
Preferred compounds according to the first, third, and fourth groups of compounds are also those where R9 is H.
Preferred compounds of the fourth group of compounds include those where R1 is an xe2x80x94OR15 group and R15 is selected from substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, or substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups.
Other particularly preferred inhibitors of VEGF-RTK are compounds having the structure II, tautomers of the compounds, pharmaceutically acceptable salts of the compounds, and pharmaceutically acceptable salts of the tautomers. Structure II has the following formula: 
In compounds having structure II, Y is selected from H, xe2x80x94OH, xe2x80x94OR10 groups, xe2x80x94SH, xe2x80x94SR11 groups, xe2x80x94NR12R13 groups, xe2x80x94CN, xe2x80x94C(xe2x95x90O)xe2x80x94R14 groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted aralkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups.
In preferred compounds of structure II, Y is selected from H, xe2x80x94OH, xe2x80x94OR9 groups, or xe2x80x94NR11R12 groups. More preferably, Y is a xe2x80x94NR11R12 group. Still more preferably, Y is a xe2x80x94NR11R12 group and both R11 and R12 are hydrogen. In other preferred compounds having the structure II, Y is selected from xe2x80x94N(CH3)2, xe2x80x94NH(CH3), xe2x80x94NH(CH2CH3), xe2x80x94N(CH2CH3)2, xe2x80x94NH(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94NH NH2, xe2x80x94NHN(CH3)2, xe2x80x94N(CH3)NH(CH3), xe2x80x94NH(CH2)mNH2 groups, xe2x80x94NH(CH2)mNH(alkyl) groups, xe2x80x94NH(CH2)mN(alkyl)2 groups, xe2x80x94N(alkyl)(CH2)mNH2 groups, xe2x80x94N(alkyl)(CH2)mNH(alkyl) groups, xe2x80x94N(alkyl)(CH2)mN(alkyl)2 groups, xe2x80x94NH(CH2)n(heterocyclyl) groups, xe2x80x94N(alkyl)[(CH2)n(heterocyclyl)] groups, xe2x80x94NH(CH2)mOH groups, xe2x80x94NH(CH2)mOCH3 groups, xe2x80x94NHCH2CH(NH2)CH(CH3)2, xe2x80x94NH(2-aminocyclohexyl), xe2x80x94NH(cyclohexyl), xe2x80x94NHOCH3, xe2x80x94NH(N-morpholinyl), xe2x80x94NH(quinuclidyl), especially xe2x80x94NH(quinuclid-3-yl), and groups where R11 and R12 join to form a substituted or unsubstituted saturated 5 or 6 membered N-containing ring, where m is 2, 3, or 4 and n is 0, 1, 2, or 3. Still more preferred compounds of this type are those in which Y is selected from xe2x80x94NH(5-benzimidazolyl), xe2x80x94NH(CH2)2N(CH3)2, xe2x80x94NH(CH2)2OH, xe2x80x94NH(CH2)(4-imidazolyl), xe2x80x94NH(CH2)(3-imidazolyl), xe2x80x94NH(CH2)(4-pyridyl), xe2x80x94NH(CH2)(2-pyridyl), xe2x80x94NH(CH2)(3-pyridyl), xe2x80x94NH(CH2)(2-tetrahydrofuranyl), xe2x80x94NH(CH2)(4-piperidinyl), xe2x80x94NH(CH2)(3-piperidinyl), xe2x80x94NH(CH2)2[2-(N-methyl-pyrrolidinyl)], xe2x80x94NH(CH2)2(2-pyrrolidinyl), xe2x80x94NH(CH2)[2-(N-methylpyrrolidinyl)], xe2x80x94NH(CH2)(2-pyrrolidinyl), xe2x80x94NH(3-piperidinyl), or xe2x80x94NH(3-pyrrolidinyl).
In compounds of structure II, X1, X2, X3, and X4 are selected from C or N and at least one of X1, X2, X3, and X4 is N. In some preferred compounds of structure II, X1 is N, R5 is absent or H, and X2, X3, and X4 are all C. In other preferred compounds of structure II, X2 is N, R6 is absent or H, and X1, X3, and X4 are C. In other preferred compounds of structure II, X3 is N, R7 is absent or H, and X1, X2, and X4 are all C. In still other preferred compounds of structure II, X4 is N, R8 is absent or H, and X1, X2, and X3 are all C.
In compounds of structure II, R1, R2, R3, R4, R5, R6, R7, and R8 may be the same or different and are independently selected from H, Cl, Br, F, I, xe2x80x94NO2, xe2x80x94CN, xe2x80x94OH, xe2x80x94OR15 groups, xe2x80x94NR16R17 groups, xe2x80x94C(xe2x95x90O)R18 groups, xe2x80x94SH, xe2x80x94SR19 groups, xe2x80x94S(xe2x95x90O)R20 groups, S(xe2x95x90O)2R21 groups, substituted or unsubstituted amidinyl groups, substituted or unsubstituted guanidinyl groups, substituted or unsubstituted primary, secondary, or tertiary alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups. In compounds of structure II, R5 is absent or is H if X1 is N, R6 is absent or is H if X2 is N, R7 is absent or is H if X3 is N, and R8 is absent or is H if X4 is N.
Some preferred compounds have the structure II where at least one of R1, R2, R3, R4, R5, R6, R7, or R8 is a substituted or unsubstituted heterocyclyl group, and, in more particular embodiments, a substituted or unsubstituted heterocyclyl group selected from morpholine, piperazine, piperidine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyrrolidine, pyrazole, pyrrole, thiomorpholine, homopiperazine, benzimidazole, oxazolidin-2-one, pyrrolidin-2-one, imidazole, isoxazole, oxazole, isothiazole, thiazole, thiophene, furan, pyran, tetrahydrothiophene, tetrahydrofuran, tetrahydropyran, and pyridine.
Still other preferred compounds having structure II are those in which R1, R2, R3, and R4 are H. In some preferred embodiments, R1 is selected from H, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyloxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-, heterocyclyl-, or aryl-aminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkyl- or aryl-aminoalkoxy groups, substituted or unsubstituted dialkylaminoalkoxy groups, or substituted or unsubstituted diarylaminoalkoxy groups. In other preferred compounds, R1 is selected from F, Cl, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-, heterocyclyl-, or aryl-aminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylaminoalkoxy groups, substituted or unsubstituted arylaminoalkoxy groups, substituted or unsubstituted dialkylaminoalkoxy groups, substituted or unsubstituted diarylaminoalkoxy groups, or substituted or unsubstituted (alkyl)(aryl)aminoalkoxy groups. Particular examples include: xe2x80x94OCH3, xe2x80x94OCH2CH2(N-morpholinyl), xe2x80x94N-morpholinyl, xe2x80x94N-cis-dimethylmorpholinyl, xe2x80x94Nxe2x80x94(4-alkyl)piperazinyl, xe2x80x94OCH2CH2N(alkyl)2 groups, xe2x80x94OCH2CH2NH(alkyl) groups, xe2x80x94OCH2CH2NH2, xe2x80x94OCH2CH2NH(aryl) groups, xe2x80x94OCH2CH2N(aryl)2 groups, alkoxy groups, xe2x80x94OCH2CH2N(alkyl)(aryl) groups, xe2x80x94O(4-piperidinyl), xe2x80x94O[4-(1-alkyl) piperidinyl] groups, xe2x80x94O[3-(1-alkyl)piperidinyl] groups, xe2x80x94O[3-quinuclidinyl], xe2x80x94OCH2(2-pyridyl), xe2x80x94OCH2(4-pyridyl), xe2x80x94O(3-pyrrolidinyl), xe2x80x94O[3-(1-alkyl) pyrrolidinyl], or other xe2x80x94O(heterocyclyl) groups not listed in this paragraph.
In other compounds having the structure II, R2 is selected from F, Cl, xe2x80x94NO2, xe2x80x94OCH3, xe2x80x94N-morpholinyl, xe2x80x94N-cis-dialkylmorpholinyl, xe2x80x94Nxe2x80x94(4-alkyl) piperazinyl, or xe2x80x94OCH2(2-pyridyl). In yet other compounds having the structure II, R2 is selected from H, F, Cl, xe2x80x94NO2, substituted or unsubstituted heterocyclylalkoxy groups, or substituted or unsubstituted heterocyclyl groups. Yet other preferred compounds having the structure II include those where R2 is selected from F, Cl, xe2x80x94NO2, substituted or unsubstituted alkoxy groups, substituted or unsubstituted heterocyclylalkoxy groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted alkyl-, heterocyclyl-, and aryl-aminoalkyl groups, substituted or unsubstituted dialkyl- and diaryl-aminoalkyl groups, substituted or unsubstituted alkylarylaminoalkyl groups, substituted or unsubstituted alkyl- and aryl-aminoalkoxy groups, substituted or unsubstituted dialkyl- and diaryl-aminoalkoxy groups, or substituted or unsubstituted alkylarylaminoalkoxy groups.
In some preferred compounds having structure II, at least two of X1, X2, X3, and X4 are C and the corresponding substituents R5, R6, R7, and R8 are hydrogen, and at least one of X1, X2, X3, and X4 is N. In yet other preferred compounds having structure II, three of R5, R6, R7, and R8 are hydrogen and one of X1, X2, X3, and X4 is N. In still other more preferred compounds of structure II, R6, R7, or both R6 and R7 are alkyl groups such as those having from one to four carbon atoms. In yet other preferred compounds of structure II, R6 or R7 is an xe2x80x94OR14 group and R14 is an alkyl, aryl, heterocyclyl, or heterocyclylalkyl group. In still further compounds of structure II, R6 or R7 is a xe2x80x94OCH2(CH2)q(heterocyclyl) group and q is 0, 1, 2, 3, or 4. In more preferred compounds in which R6 or R7 is a xe2x80x94OCH2(CH2)q-(heterocyclyl) group, the heterocyclyl group of the xe2x80x94OCH2(CH2)n(heterocyclyl) group is a heterocycle selected from substituted or unsubstituted morpholine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted pyrrole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholine in which the S atom of the thiomorpholine group is bonded to one or more O atoms, substituted or unsubstituted homopiperazine, substituted or unsubstituted oxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyridine, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted furan, substituted or unsubstituted thiophene, substituted or unsubstituted tetrahydrofuran, substituted or unsubstituted tetrahydrothiophene, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted benzothiazole.
In compounds of structure II, R9 is selected from H, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, xe2x80x94NH2, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, or xe2x80x94C(xe2x95x90O)-aryl groups. One group of particularly preferred compounds of structure II are those in which R9 is hydrogen.
In compounds of structure II, R10 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94(C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, or xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups;
In compounds of structure II, R11 and R19 may be the same or different and are independently selected from substituted or unsubstituted alkyl groups, or substituted or unsubstituted aryl groups whereas R12 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups.
In compounds of structure II, R13 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, substituted or unsubstituted heterocyclylalkyl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkylamino groups, substituted or unsubstituted arylamino groups, substituted or unsubstituted dialkylamino groups, substituted or unsubstituted diarylamino groups, substituted or unsubstituted (alkyl)(aryl)amino groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94O-heterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups. R12 and R13 may join together to form a 5 to 7 membered saturated or unsaturated, substituted or unsubstituted N-containing ring.
In compounds of structure II, R14 is selected from H, xe2x80x94OH, alkoxy groups, aryloxy groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)2 groups, xe2x80x94N(alkyl)(heterocyclyl) groups, or xe2x80x94N(aryl)(heterocyclyl) groups.
In compounds of structure II, R15 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl group""s, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted diheterocyclylaminoalkyl groups, substituted or unsubstituted (heterocyclyl)(alkyl)aminoalkyl groups, substituted or unsubstituted (heterocyclyl)(aryl)aminoalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted hydroxyalkyl groups, or substituted or unsubstituted heterocyclyloxyalkyl groups.
In compounds of structure II, R16 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, or substituted or unsubstituted heterocyclyl groups whereas R17 is selected from H, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94C(xe2x95x90O)H, xe2x80x94C(xe2x95x90O)-alkyl groups, xe2x80x94C(xe2x95x90O)-aryl groups, xe2x80x94C(xe2x95x90O)NH2, xe2x80x94C(xe2x95x90O)NH(alkyl) groups, xe2x80x94C(xe2x95x90O)NH(aryl) groups, xe2x80x94C(xe2x95x90O)N(alkyl)2 groups, xe2x80x94C(xe2x95x90O)N(aryl)2 groups, xe2x80x94C(xe2x95x90O)N(alkyl)(aryl) groups, xe2x80x94C(xe2x95x90O)O-alkyl groups, xe2x80x94C(xe2x95x90O)O-aryl groups, substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (aryl)(alkyl)aminoalkyl groups, substituted or unsubstituted heterocyclylalkyl groups, xe2x80x94C(xe2x95x90O)-heterocyclyl groups, xe2x80x94C(xe2x95x90O)xe2x80x94Oheterocyclyl groups, xe2x80x94C(xe2x95x90O)NH(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(heterocyclyl)2 groups, xe2x80x94C(xe2x95x90O)xe2x80x94N(alkyl)(heterocyclyl) groups, xe2x80x94C(xe2x95x90O)N(aryl)(heterocyclyl) groups, substituted or unsubstituted heterocyclylaminoalkyl groups, substituted or unsubstituted hydroxyalkyl groups, substituted or unsubstituted alkoxyalkyl groups, substituted or unsubstituted aryloxyalkyl groups, substituted or unsubstituted heterocyclyloxyalkyl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, or xe2x80x94NH2 groups. R16 and R17 may join together to form a 5 to 7 membered saturated or unsaturated, substituted or unsubstituted N-containing ring.
Finally, in compounds of structure II, R18, R20, and R21 may be the same or different and are independently selected from H, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94NH(aryl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94OH, substituted or unsubstituted alkoxy groups, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclyl groups, xe2x80x94NHOH, xe2x80x94N(alkyl)OH groups, xe2x80x94N(aryl)OH groups, xe2x80x94N(alkyl)O-alkyl groups, xe2x80x94N(aryl)O-alkyl groups, xe2x80x94N(alkyl)O-aryl groups, or xe2x80x94N(aryl)O-aryl groups.
Compounds having the structure II may include those in which R18 is selected from substituted or unsubstituted alkyl groups, substituted or unsubstituted aryl groups, xe2x80x94NH2, xe2x80x94NH(alkyl) groups, xe2x80x94N(alkyl)2 groups, xe2x80x94NH(aryl) groups, xe2x80x94N(aryl)2 groups, xe2x80x94N(alkyl)(aryl) groups, xe2x80x94NH(heterocyclyl) groups, xe2x80x94N(heterocyclyl)(alkyl) groups, N(heterocyclyl)(aryl) groups, xe2x80x94N(heterocyclyl)2 groups, or N-containing heterocycles, and the N-containing heterocycles are bonded to the carbonyl carbon of the xe2x80x94C(xe2x95x90O)xe2x80x94R18 group through either a nitrogen atom or a carbon atom in the rings of the N-containing heterocycles. In still more preferred compounds in which R18 is a N-containing heterocycle, the N-containing heterocycle of the R18 group is selected from substituted or unsubstituted morpholine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted pyrrole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiomorpholine, substituted or unsubstituted homopiperazine, substituted or unsubstituted oxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyridine, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted benzothiazole.
Other preferred compounds having structure II are provided in which R15 or R17 is selected from substituted or unsubstituted aminoalkyl groups, substituted or unsubstituted alkylaminoalkyl groups, substituted or unsubstituted arylaminoalkyl groups, substituted or unsubstituted dialkylaminoalkyl groups, substituted or unsubstituted diarylaminoalkyl groups, substituted or unsubstituted (alkyl)(aryl)aminoalkyl groups, or substituted or unsubstituted heterocyclylaminoalkyl groups including: xe2x80x94CH2(CH2)pNH2 groups, xe2x80x94CH2(CH2)pNH(alkyl) groups, xe2x80x94(H2(CH2)pNH(aryl) groups, xe2x80x94CH2(CH2)pN(alkyl)2 groups, xe2x80x94CH2(CH2)pN(aryl)2 groups, xe2x80x94CH2(CH2)pN(alkyl)(aryl) groups, or xe2x80x94CH2(CH2)p(heterocyclyl) groups, where p is an integer ranging from 0 to 4 and the heterocyclyl group of the xe2x80x94CH2(CH2)p(heterocyclyl) group is a N-containing heterocycle selected from substituted or unsubstituted morpholine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted piperazine, substituted or unsubstituted piperidine, substituted or unsubstituted pyrrole, substituted or unsubstituted imidazole, substituted or unsubstituted pyrazole, substituted or unsubstituted 1,2,3-triazole, substituted or unsubstituted 1,2,4-triazole, substituted or unsubstituted tetrazole, substituted or unsubstituted thiomorpholine, substituted or unsubstituted homopiperazine, substituted or unsubstituted oxazolidin-2-one, substituted or unsubstituted pyrrolidin-2-one, substituted or unsubstituted pyridine, substituted or unsubstituted oxazole, substituted or unsubstituted isoxazole, substituted or unsubstituted thiazole, substituted or unsubstituted isothiazole, substituted or unsubstituted benzimidazole, substituted or unsubstituted benzoxazole, or substituted or unsubstituted benzothiazole.
Compounds of structure I are readily synthesized from simple starting molecules as shown in the following Examples. Compounds of structure I may generally be prepared using benzene substituted with nitrile or carboxylic acid groups in addition to other optional groups.
Compounds of structure I may be synthesized from simple starting molecules as shown in Schemes 1-4 and exemplified in the Examples. As shown in Scheme 1, compounds of structure I may generally be prepared using aromatic compounds substituted with amines and carboxylic acid groups. 
As shown in Scheme 1, a substituted aromatic compound such as a substituted or unsubstituted 2-aminobenzoic acid may be reacted with an acyl halide such as methyl 2-(chlorocarbonyl)acetate to produce an amide that will react with a substituted or unsubstituted 1,2-diaminobenzene. The resulting product is a 4-hydroxy-substituted compound of structure I. One skilled in the art will recognize that the procedure set forth in Scheme 1 may be modified to produce various compounds.
A method for preparing 4-amino substituted compounds of structure I is shown in Scheme 2. As shown in Scheme 2, aromatic compounds substituted with amine and nitrile groups may be used to synthesize 4-amino substituted compounds of structure I. A compound such as ethyl 2-cyanoacetate may be reacted with ethanol to produce ethyl 3-ethoxy-3-iminopropanoate hydrochloride. Subsequent reaction with a substituted or unsubstituted 1,2-phenylenediamine provides substituted or unsubstituted ethyl 2-benzimidazol-2-ylacetate. Reaction of a substituted or unsubstituted ethyl 2-benzimidazol-2-ylacetate with an aromatic compound having an amine and nitrile group such as substituted or unsubstituted 2-aminobenzonitrile with a base such as lithium bis(trimethylsilyl)amide or a Lewis acid such as tin tetrachloride provides the substituted or unsubstituted 4-amino substituted compound of structure I. 
Scheme 3 illustrates a general synthetic route that allows for the synthesis of 4-dialkylamino and 4-alkylamino compounds of structure I. An inspection of Scheme 3 shows that 4-hydroxy substituted compounds of structure I may be converted into the 4-chloro derivative by reaction with phosphorous oxychloride or thionyl chloride. The 4-chloro derivative may then be reacted with an alkylamine or dialkylamine to produce the corresponding 4-alkylamino or 4-dialkylamino derivative. Deprotection affords the final 4-alkylamino or 4-dialkylamino compounds of structure I. Other groups that may be reacted with the 4-chloro derivative in this manner include, but are not limited to, ROH, RSH, and CuCN. 
As shown in Scheme 4, the synthesis of compounds of structure I having a H, alkyl group, aryl group, or heterocyclyl group in the 4-position may be accomplished using a substituted or unsubstituted 2-benzimidazol-2-ylacetate prepared as shown in Schemes 2 and 3. 
Heteroaromatic diamines may be used as precursors of compounds of structure II. The synthesis of compounds of structure II where Y=NH2 is depicted in Scheme 5. 
A compound such as ethyl cyanoacetate may be condensed with a substituted or unsubstituted heterocycle containing two ortho amino groups such as substituted or unsubstituted 1,2-diaminopyridine to obtain a substituted or unsubstituted 2-imidazolo[5,4-b]pyridin-2-ylethanenitrile, which may subsequently be hydrolyzed in acidic medium to provide a substituted or unsubstituted ethyl 2-imidazolo[5,4-b]pyridin-2-ylacetate. As an alternate route, a substituted or unsubstituted ethyl 2-imidazolo[5,4-b]pyridin-2-ylacetate may be obtained from a compound such as the hydrochloride salt of 3-ethoxy-3-iminopropanoate and a substituted or unsubstituted 1,2-diaminopyridine. Reaction of a substituted or unsubstituted ethyl 2-imidazolo[5,4-b]pyridin-2-ylacetates with an aromatic compound having an amine and nitrile group such as substituted or unsubstituted 2-aminobenzonitrile with a base such as lithium bis(trimethylsilyl)amide provides the substituted or unsubstituted compound of structure II.
The instant invention also provides for compositions which may be prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like, to treat or ameliorate a variety of disorders related to the activity of VEGF-RTK, more particularly angiogenesis associated with cancer. A therapeutically effective dose further refers to that amount of one or more compounds of the instant invention sufficient to result in amelioration of symptoms of the disorder. The pharmaceutical compositions of the instant invention can be manufactured by methods well known in the art such as conventional granulating, mixing, dissolving, encapsulating, lyophilizing, emulsifying or levigating processes, among others. The compositions can be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The instant compositions can be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration, or subcutaneous administration as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular injection. The compound or compounds of the instant invention can also be administered in a local rather than a systemic fashion, such as injection as a sustained release formulation. The following dosage forms are given by way of example and should not be construed as limiting the instant invention.
For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient such as a starch or other additive. Suitable additives or excipients are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methyl cellulose, hydroxypropylmethyl-cellulose, and/or polyvinylpyrrolidone. Optionally, oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyestuffs or pigments may be added for identification. Tablets and pills may be further treated with suitable coating materials known in the art.
Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, slurries and solutions, which may contain an inactive diluent, such as water. Pharmaceutical formulations may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents, may be added for oral or parenteral administration.
As noted above, suspensions may include oils. Such oil include, but are not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, such as but not limited to, poly(ethyleneglycol), petroleum hydrocarbons such as mineral oil and petrolatum; and water may also be used in suspension formulations.
For nasal administration, the pharmaceutical formulations may be a spray or aerosol containing and appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these. A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide, or a hydrocarbon based low boiling solvent. The compound or compounds of the instant invention are conveniently delivered in the form of an aerosol spray presentation from a nebulizer or the like.
Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer""s solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
For injection, the pharmaceutical formulation may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or in multi-dose containers.
For rectal administration, the pharmaceutical formulations may be in the form of a suppository, an ointment, an enema, a tablet or a cream for release of compound in the intestines, sigmoid flexure and/or rectum. Rectal suppositories are prepared by mixing one or more compounds of the instant invention, or pharmaceutically acceptable salts or tautomers of the compound, with acceptable vehicles, for example, cocoa butter or polyethylene glycol, which is present in a solid phase at normal storing temperatures, and present in a liquid phase at those temperatures suitable to release a drug inside the body, such as in the rectum. Oils may also be employed in the preparation of formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerols may be employed in the preparation of suspension formulations which may also contain suspending agents such as pectins, carbomers, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, as well as buffers and preservatives.
Besides those representative dosage forms described above, pharmaceutically acceptable excipients and carries are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in xe2x80x9cRemingtons Pharmaceutical Sciencesxe2x80x9d Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
The formulations of the invention may be designed for to be short-acting, fast-releasing, long-acting, and sustained-releasing as described below. Thus, the pharmaceutical formulations may also be formulated for controlled release or for slow release.
The instant compositions may also comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the pharmaceutical formulations may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers.
Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant invention.
A therapeutically effective dose may vary depending upon the route of administration and dosage form. The preferred compound or compounds of the instant invention is a formulation that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects which can be expressed as the ratio between LD50 and ED50. The LD50 is the dose lethal to 50% of the population and the ED50 is the dose therapeutically effective in 50% of the population. The LD50 and ED50 are determined by standard pharmaceutical procedures in animal cell cultures or experimental animals.
xe2x80x9cTreatingxe2x80x9d within the context of the instant invention, means an alleviation of symptoms associated with a disorder or disease, or halt of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. For example, within the context of treating patients in need of an inhibitor of VEGF-RTK, successful treatment may include a reduction in the proliferation of capillaries feeding a tumor or diseased tissue, an alleviation of symptoms related to a cancerous growth or tumor, proliferation of capillaries, or diseased tissue, a halting in capillary proliferation, or a halting in the progression of a disease such as cancer or in the growth of cancerous cells. Treatment may also include administering the pharmaceutical formulations of the present invention in combination with other therapies. For example, the compounds and pharmaceutical formulations of the present invention may be administered before, during, or after surgical procedure and/or radiation therapy. The compounds of the invention can also be administered in conjunction with other anti-cancer drugs including those used in antisense and gene therapy.
A method of treating a patient in need of an inhibitor of vascular endothelial growth factor receptor tyrosine kinase includes administering an effective amount of a pharmaceutical formulation according to the invention to a patient in need thereof.
A method for inhibiting tumor growth in a patient includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a patient having a tumor.
A method for inhibiting the proliferation of capillaries in a patient includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof according to a patient in need.
A method of preparing pharmaceutical formulations includes mixing any of the above-described compounds with a pharmaceutically acceptable carrier and water or an aqueous solution.
The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.